Thiazoloquinoxalines

ABSTRACT

Heterocyclic dihydroxyquinoxaline compounds having the formula ##STR1## wherein R 2  is hydrogen, NO 2 , NH 2 , CN, halogen, or SO 2  NH 2  ; 
     --X--Y--Z-- is selected from --S--CR 3  ═N--, --N═CR 3  --S-- 
     wherein R 3  is hydrogen, lower alkyl, or CF 3 . 
     The invention also relates to a method of preparing the compounds, pharmaceutical compositions thereof, and their use. 
     The compounds are useful in the treatment of indications caused by hyperactivity of the excitatory neurotransmitters.

This is a division of application Ser. No. 369,762, filed June 22, 1989,now U.S. Pat. No. 4,977,155, issued 12-11-90.

The present invention relates to therapeutically active heterocycliccompounds, a method of preparing the same, pharmaceutical compositionscomprising the compounds, and a method of treating therewith.

The heterocyclic compounds of the invention have the general formula I##STR2## wherein R² is hydrogen, NO₂, NH₂, CN, halogen, or SO₂ NH₂ ;

--X--Y--Z-- is selected from

--N═N--NR³ --,--NR³ --N═N--,═N--NR³ --N═,--S--CH═N--,--N═CH--S--,--CH═C(CO₂ R³)--S--, --S--C(CO₂ R³)═CH--,═N--Se--N═, --N═CR³ --NR³--,--NR³ --CR³ ═N--, ═N--O--N═, --N═CR³ --CR³ ═N--,--NH--CR³ ═CR³ --CR³═N--,--N═CR³ --CR³ ═CR³ --NH,═N--S--N═; wherein R³ is hydrogen, loweralkyl, or CF₃.

The compounds of the invention can be prepard by methods well known inthe art and for example by:

a) reacting a compound having the formula II ##STR3## wherein--X--Y--Z--, R² and R³ have the meanings set forth above, with oxalateor a reactive derivative thereof to form a compound of formula I, or

b) refluxing a compound having the formula III ##STR4## wherein--X--Y--Z--, R² and R³ have the meanings defined above, and wherein R⁴is lower alkyl, in a mineral acid, to form a compound of formula I.

L-glutamic acid, L-aspartic acid and a number of other closely relatedamino acids have in common the ability to activate neurons in thecentral nervous system (CNS). Biochemical, electrophysiological andpharmacological studies have substantiated this and demonstrated thatacidic amino acids are transmitters for the vast majority of excitatoryneurons in the mammalian CNS.

Interaction with glutamic acid mediated neurotransmission is considereda useful approach in the treatment of neurological and psychiatricdiseases. Thus, known antagonists of excitatory amino acids have shownpotent antiepileptic and muscle relaxant properties (A. Jones et al.,Neurosci. Lett. 45, 157-61 (1984) and L. Turski et al., Neurosci. Lett.53, 321-6 (1985) ).

It has been suggested that accumulation of extracellular excitatory andneurotoxic amino acids, followed by hyperstimulation of neurons, mayexplain the neuronal degenerations seen in neurological diseases asHuntingtons chorea, Parkinsonism, epilepsia, senile dementia, anddeficiencies of mental and motoric performance seen after conditions ofbrain ischemia, anoxia and hypoglycemia (E. G. McGeer et al.. Nature.263, 517-19 (1976) and R. Simon et al., Science, 226, 850-2 (1984).

Excitatory amino acids exert their actions via specific receptorslocated postsynaptically or presynaptically. Such receptors are atpresent conveniently subdivided into three groups based onelectrophysiological and neurochemical evidence: 1 the NMDA(N-methyl-D-aspartate) receptors, 2 the quisqualate receptors, and 3 thekainate receptors. L-glutamic acid and L-aspartic acid probably activateall the above types of excitatory amino acid receptors and possiblyother types as well.

The consequence of excitatory amino acid interaction with postsynapticreceptors is an increase in intracellular cGMP levels (G. A. Foster etal., Life Sci. 27, 215-21 (1980) ) and an opening of Na⁺ -channels (A.Luini et al., Proc. Natl. Acad. Sci. 78, 3250-54 (1981)). Na⁺ -influx inthe neurons will depolarize the neuronal membranes, initiate an actionpotential and ultimately lead to a release of transmitter substance fromthe nerve terminal. The effects of test compounds on the above mentionedsecondary responses to receptor interaction can be tested in simple invitro systems.

The above mentioned classification of excitatory amino acid receptorsinto NMDA, quisqualate, and kainate receptors is based primarily on thefollowing electrophysiological and neurochemical findings.

1) N-methyl-D-aspartate (NMDA) receptors exhibit high selectivity forthe excitant NMDA. Ibotenic acid, L-homocysteic acid, D-glutamic acidand trans-2,3-piperidine dicarboxylic acid (trans-2,3-PDA) exert astrong to moderate agonist activity on these receptors. The most potentand selective antagonists are the D-isomers of the2-amino-5-phosphonocarboxylic acids, e.g., 2-amino-5-phosphono-valericacid (D-APV) and 2-amino-7-phosphonoheptanoic acid (D-APH), whilemoderate antagonist activity is shown by the D-isomers of long chain2-amino dicarboxylic acids (e.g., D-2-amino-adipic acid) and long chaindiaminodicarboxylic acids (e.g., diaminopimelic acid). The NMDA-inducedsynaptical responses have been extensively investigated in the mammalianCNS, especially in the spinal cord (J. Davies et al., J. Physiol. 297,621-35 (1979) and the responses have been shown to be strongly inhibitedby Mg²⁺.

It is well known that NMDA antagonists have anticonvulsant activityagainst seizures of diverse origin (Jones et al., Neurosci. Lett. 45,157-61 (1984)), and that the potencies of the substances in seizuretests correlate well with the ability of the compounds to block NMDAresponces in in vivo and in vitro electrophysiological experiments(Watkins et al., Annu. Rev. Pharmacol. Toxicol. 21, 165-204 (1981)).

NMDA antagonists are therefore useful as anticonvulsants, especially asanti-epileptics.

2) Quisqualate receptors are activated selectively by quisqualic acid,other potent agonists being AMPA(2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and L-glutamicacid. Glutamic acid diethyl ester (GDEE) is a selective but very weakantagonist of this site. Quisqualate receptors are relativelyinsensitive to Mg²⁺.

It is well known that an excitatory aminoacid projection from prefrontalcortex to nucleus accumbens (a special part of the forebrain havingdopamine neurons) exists (Christie et al., J. Neurochem. 45, 477-82(1985)). Further it is well known that glutamate modulates thedopaminergic transmission in the striatum (Rudolph et al., Neurochem.int. 5, 479-86 (1983)) as well as the hyperactivity connected withpresynaptic stimulation of the dopamine system with AMPA in nucleusaccumbens (Arnt. Life Sci. 28, 1597-1603 (1981)).

Quisqualate antagonists are therefore useful as a new type ofneuroleptic.

3) Kainate receptors. Excitatory responses to kainic acid are relativelyinsensitive to antagonism by NMDA-antagonists and by GDEE, and it hasbeen proposed that kainic acid activates a third subclass of acidicamino acid receptor. Certain lactonized derivatives of kainic acid areselective antagonists (O. Goldberg et al., Neurosci. Lett. 23, 187-91(1981)) and the dipeptide 3-glutamyl-glycine also shows some selectivityfor kainate receptors. Ca²⁺ but not Mg²⁺ is a strong inhibitor of kainicacid binding.

The affinity of a substance for one or more of the different types ofexcitatory amino acid receptors may be studied in simple bindingexperiments. In essense, the method involves incubation of a particularselected radiolabelled ligand and the particular specific substance tobe investigated with brain homogenate which contains the receptor.Measurement of receptor occupancy is made by determination of theradioactivity bound to the homogenate and subtraction of nonspecificbinding.

The influence of glutamic acid analogues on secondary effects ofglutamate receptor interactions, such as on c-GMP formation and on Na⁺-efflux, may be studied in vitro by using brain slices. Such experimentswill provide information as to the efficacies (agonist/antagonist) ofthe test substances. This is in contrast to binding studies, which onlyprovide information on the affinities of the compounds for the receptor.

It has now been found that the heterocyclic compounds of the inventionhave affinity for the glutamate receptors and are antagonists inconnection with these types of receptors, which makes them useful in thetreatment of any of the numerous indications caused by hyperactivity ofexcitatory amino acids.

The quisqualate receptor binding activity of the compounds of thepresent invention can be illustrated by determining their capability fordisplacing radioactively labelled2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) from thequisqualate type receptors.

The quisqualate antagonistic properties of the compounds is demonstratedby their capability to antagonize quisqualic acid stimulated Na⁺ -effluxfrom rat striatal slices.

The NMDA antagonistic properties of the compounds is illustrated bydetermining their capability to antagonize NMDA stimulated ³ H-GABArelease from cultured mouse cortex neurons.

The displacement activity of the compounds may be shown by determiningthe IC₅₀ value which represents the concentration (μg/ml) which causes adisplacement of 50% of the specific binding of ³ H-AMPA.

The quisqualate antagonism is measured by determining the EC₅₀ valuewhich represents the concentration which reduces the rate of quisqualicacid stimulated sodium efflux by 50%.

The NMDA antagonistic activity of the compounds may be shown bydetermining the IC₅₀ value, which represents the concentration (μg/ml)which inhibits 50% of NMDA induced ³ H-GABA release.

³ H-AMPA binding (Test 1)

500 μl of thawed rat cerebral cortical membrane homogenate in Tris-HCl(30 mM), CaCl₂ (2.5 mM) and KSCN (100 mM) pH 7.1 were incubated at 0° C.for 30 min. with 25 μl ³ H-AMPA (5 nM final concentration) and the testcompound and buffer. Nonspecific binding was determined by incubationwith L-glutamic acid (600 μM final concentration). The binding reactionwas terminated by adding 5 ml of ice-cold buffer followed by filtrationthrough Whatman GF/C glass fibre filters and 2×5 ml wash with ice-coldbuffer. Bound radioactivity was measured by scintillation counting. IC₅₀was determined by Hill analysis of at least four concentrations of testcompound.

Antagonism of quisqualic acid induced ²² Na⁺ -release (Test 2)

Slices from rat striatum were preincubated with ²² Na⁺ for 30 min. Afterthe ²² Na⁺ loading period, the slices were successively and every minutetransferred through a series of tubes, each containing 1.5 ml of anon-radioactive physiological solution saturated with O₂, with the helpof a basket shaped sieve. Quisqualic acid (2 μg/ml) was present in thelast 5 tubes and the compound to be tested was present in the same 5tubes plus 3 tubes before. The amount of radioactivity in each washouttube as well as that left in the slices at the end of the experiment wasmeasured by scintillation counting. EC₅₀ -values were calculated by Hillanalysis from at least three different concentrations of test compoundas the concentration of test compound which reduces the efflux rate of²² Na⁺ -ions to 50% of the efflux rate in the absence of test compound.

Inhibition of NMDA stimulated ³ H-GABA release from cultured mousecerebral cortex interneurons (Test 3)

Release experiments are performed using the model described by Drejer etal. (Life Sci. 38, 2077 (1986)). To cerebral cortex interneuronscultured in petri dishes (30 mm) are added 100 μg/ml 3-vinyl-GABA onehour before the experiment in order to inhibit degradation of GABA inthe neurons. 30 min before the experiment 5 μCi ³ H-GABA is added toeach culture and after this preloading period the cells are washed twicewith a HEPES (N-2 Hydroxyethylpiperazine-N'-2-ethanesulfonic acid)buffered saline (HBS) containing 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6mM MgSO₄, 1.0 mM CaCl₂ and 6 mM D-glucose; pH 7 and placed in asuperfusion system. This system consists of a peristaltic pumpcontinuously delivering thermostated 37° C. superfusion medium from areservoir to the top of a slightly-tilted petri dish. The cell monolayerat the bottom of the dish is covered with a piece of nylon mesh tofacilitate dispersion of medium over the cell layer. The medium iscontinuously collected from the lower part of the dish and delivered toa fraction collector. Initially, the cells are superfused with HBS for15 min (flow rate 2 ml/min). Then cells are stimulated for 30 sec every4 min by changing the superfusion medium from HBS to a correspondingmedium containing NMDA and antagonists according to the followingscheme:

stimulation no. 1: 3 μg/ml NMDA

stimulation no. 2: 3 μg/ml NMDA+0.3 μg/ml antagonist

stimulation no. 3: 3 μg/ml NMDA+3 μg/ml antagonist

Test substances are dissolved in water or 48% ethanol. The final ethanolconcentration in the assay must not exceed 0.1%.

The release of ³ H-GABA in the presence of NMDA (stimulated relase incpm) are corrected for the mean basal release (cpm) before and after thestimulation.

The stimulated release in the presence of antagonists are expressedrelative to the stimulated release by NMDA alone and the IC₅₀ value forthe antagonist is calculated (the concentration (μg/ml) of the testsubstance which inhibits 50% of the NMDA induced ³ H-GABA release)either from a dose response curve or from the formula: ##EQU1## whereC_(o) is stimulated release in control assays and C_(x) is thestimulated release in the test assay (the calculation assumes normalmass-action interaction). 25-75% inhibition of the NMDA stimulation mustbe obtained, before calculation of IC₅₀.

Test results obtained by testing some compounds employed in the presentinvention will appear from the following table 1.

                  TABLE l                                                         ______________________________________                                        Compound                                                                      of         Test 1     Test 2      Test 3                                      Example    IC.sub.50 μg/ml                                                                       EC50 μg/ml                                                                             IC.sub.50 μg/ml                          ______________________________________                                        Ex 1:      13,3                                                               Ex 2:      0,85       10          0,26                                        Ex 4:      10                                                                 Ex 6:      0,31       4,1         0,096                                       Ex 9       0,41                   0,14                                        Ex 11:     0,36                   0,14                                        Ex 13:     0,07                   0,11                                        Ex 15:     0,19                   0,73                                        Ex 17:     0,21                                                               Ex 24:     0,23                   0,13                                        Ex 35:     0,39                   0,1                                         Ex 36:     0,39                   0,14                                        Ex 38:     0,13                   0,09                                        Ex 39:     1,9                                                                ______________________________________                                    

The invention will now be described in further detail with reference tothe following examples.

EXAMPLE 1 7,8 Dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline

A suspension of 4-amino-5-nitrobenzotriazole (0.72 g, 4 mmol) in 100 mlof ethanol and 1 ml of conc. hydrochloric acid was hydrogenated atatmospheric pressure and room temperature for 6 h in the presence of 100mg of 5% palladium-on-charcoal. The mixture was filtered and thecatalyst was washed with about 50 ml of water. The combined filtrate wasevaporated to dryness giving 0.70 g of the 4,5-diamino-benzotriazole asan hydrochloride. A solution of the crude diamino compound in 40 ml of4M hydrochloric acid was refluxed with oxalic acid dihydrate (0.50 g, 4mmol) for 3 h. The mixture was cooled on ice, and pH was adjusted to 5-6with 2N sodium hydroxide. The precipitate was filtered off and washedwith water and ethanol. It was then dissolved in 10 ml of 2N sodiumhydroxide, treated with decolourising charcoal, and filtered. Afteradjustment to pH 6-7 with 4M hydrochloric acid the reprecipitatedproduct was isolated, washed with water and ethanol, and dried at 100 °C. affording 0.12 g (15%) of pure title compound; m.p.>300° C.; IR(KBr): 3200-2000, 1670 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 6.9 (broad s, 3H,NH+2OH); 7.03 (d,J=8 Hz, 1H, ArH); 7.43 (d,J=8 Hz,1H, ArH).

EXAMPLE 2 7,8-Dihydroxy-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline

Finely powdered potassium nitrate (3.1 q, 30.7 mmol) was added to astirred solution of 7,8-dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline(6.1 g, 30 mmol) in 50 ml of conc. sulfuric acid at 0° C. (ice bath).The mixture was stirred over night at room temperature. Then a furtheramount of potassium nitrate (3 g) was added with cooling on an ice bath,and stirring was continued for 5 h at room temperature. The mixture waspoured into 700 ml of ice/water, and the yellow precipitate wasisolated, washed with water, and recrystallized from ethanol giving 5.2g (70%) of the title compound; m.p.>300° C.; IR (KBr): 3300-2200, 1700cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 8.13 (s, 1H, ArH), 11-16 (broad, ³ H, NH+2OH).

EXAMPLE 3 4-Amino-7,8-dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of stannous chloride dihydrate (6.0 g, 26.6 mmol) in 27 ml ofconc. hydrochloric acid was added dropwise to a stirred suspension of7,8-dihydroxy-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline (2.0 g, 8.1mmol) in 13 ml of conc. hydrochloric acid. The mixture was stirred at60° C. for 2 h, and then cooled on an ice bath. The precipitate wasisolated by filtration and washed with cold conc. hydrochloric acid. Thecrude product was dissolved in 40 ml of hot 2N sodium hydroxide,filtered while hot, and adjusted to pH 5-6 with 4M hydrochloric acid.The precipitated solid was filtered, washed with water and dried toyield 1.63 g (93%) of the amino compound, m.p.>300° C., IR (KBr): 3450,3350, 3230-2200, 1700-1600 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 5.8 (broad s, 2H,NH₂), 6.28 (s, 1H, ArH).

EXAMPLE 4 4-Cyano-7,8-dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline

4-Amino-7,8-dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline (0.44 g, 2mmol) was suspended in 20 ml of 2M sulfuric acid and diazotised at 0° C.with sodium nitrite (0.18 g, 2.6 mmol) in 4 ml of water. After stirringat 0° C. for 30 min the diazo-suspension was adjusted to pH 7 with solidsodium hydrogen carbonate, and a solution of potassiumtetracyanonickelate (1.3 g) in 20 ml of water was added in one portion.Stirring was continued for 1 h at 0° C. and then the mixture was heatedon a steam-bath for 30 min. After cooling on ice, the mixcture wasadjusted to pH 5 and filtered. The isolated dark solid was washed withwater and recrystallized from ethanol with decolourising charcoalaffording 20 mg (4.3%) of pure title compound, m.p.>300° C.; IR (KBr):3300-2300, 2240, 1690 cm⁻¹.

EXAMPLE 5 7,8-Dihydroxy-1-methyl-1H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of 6,7-diamino-1-methylbenzotriazolc (1.63 g, 10 mmol) andoxalic acid dihydrate (2.0 g, 16 mmol) in 50 ml of 4M hydrochloric acidwas refluxed on an oil bath for 2 h. The mixture was cooled on ice andthe precipitate was collected by filtration, washed with water andethanol affording 1.94 g (89%) of the title compound; m.p.>300° C.; IR(KBr): 3520-2400, 1700 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 4.63 (s, 3H, CH₃), 6.70(d, J=9 Hz, 1H; ArH), 7.60 (d, J=9 Hz, 1H, ArH), 11.3 (very broad s, 1H,OH), 12.1 (broad s, 1H, OH).

EXAMPLE 67,8-Dihydroxy-1-methyl-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline

Finely powdered potassium nitrate (0.71 g, 7 mmol) was added portionwiseto a stirred solution of7,8-dihydroxy-1-methyl-1H-1,2,3-triazolo[4,5-f]quinoxaline (1.52 g, 7mmol) in 28 ml of conc. sulfuric acid at 0° C. After about 1 h the icebath was removed and stirring was continued over night at roomtemperature. Then an additional amount of potassium nitrate (0.7 g) wasadded and the mixture was stirred for 4 h at room temperature. Now thesolution was poured into 150 ml of ice/water and the precipitated yellowsolid was isolated by filtration and washed with water.Recrystallization from water/ethanol (1:1) afforded 1.2 g (65%) of thepure nitro compound; m.p.>300° C.; IR (KBr): 3600-2500, 1720 cm⁻¹ ; ¹H-NMR (DMSO-d₆): 4.62 (s,3H, CH₃), 8.07 (s, 1H, ArH), 12.4 (broad s, 1H,OH, only one exchangeable proton could be seen).

EXAMPLE 74-Amino-7,8-dihydroxy-1-methyl-1H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of stannous chloride dihydrate (2.26 g, 10 mmol) in 10 ml ofconc. hydrochloric acid was added dropwise to a suspension of7,8-dihydroxy-1-methyl-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline (0.79g, 3 mmol) in 5 ml of conc. hydrochloric acid with stirring on an oilbath at 60°-70° C. Stirring was continued at this temperature for 90min. Then the mixture was cooled on an ice bath, and filtered. Theprecipitate was washed with 1 ml of conc. hydrochloric acid, suspendedin 150 ml of hot water, and adjusted to pH 6-7 with solid sodiumhydrogen carbonate. After reflux for 1 h the mixture was cooled on iceand the crude product was isolated by filtration, dissolved in 40 ml ofhot 2N sodium hydroxide and reprecipitated with 4M acetic acid giving0.16 g (23%) of the pure amino compound; m.p.>300° C.; IR (KBr): 3435,3350, 3240, 3100-2400, 1690, 1640 cm⁻¹.

EXAMPLE 8 7,8-Dihydroxy-1H-pyrazolo[3,4-f]quinoxaline

A solution of 6,7-diaminoindazole hydrochloride (1.0 g, 5.4 mmol) in 10ml of 4M hydrochloric acid was refluxed on an oil bath for 11/2 h. Thecooled mixture was filtered, and the isolated product was washed withwater and ethanol, and dried in vacuo over phosphorus pentoxideaffording 1.0 g (91%) of the pure title compound; m.p.>300° C.; IR(KBr): 3300-2000, 1700 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 6.3 (very broad s, 2H,NH and OH), 6.93 (d, J=9 Hz, 1H, ArH), 7.43 (d, J=9 Hz, 1H, ArH), 8.00(s, 1H, H-3), 12.1 (broad s, 1H, OH).

EXAMPLE 9 7,8-Dihydroxy-4-nitro-1H-pyrazolo[3,4-f]quinoxaline

Finely powdered potassium nitrate (0.11 g, 1 mmol) was added to astirred solution of 7,8-dihydroxy-1H-pyrazolo[3,4-f]quinoxaline (0.2 g,1 mmol) in 2 ml of conc. sulfuric acid at room temperature. The solutionwas stirred for 1 h at this temperature and then poured into 50 ml ofice/water. After 30 min the precipitated solid was isolated byfiltration and washed with water. Recrystallization fromN,N-dimethylformamide/water afforded 0.13 g (53%) of the nitro compound;m.p.>300° C.; IR (KBr): 3300-2500, 1705 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 7.83(s, 1H, ArH), 8.37 (s, 1H, ArH), 12.2 (broad s, 2H, 20H).

EXAMPLE 10 7,8-Dihydroxy-2-methyl-2H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of 4,5-diamino-2-methylbenzotriazole (2.5 g, 15.3 mmol) andoxalic acid dihydrate (2.5 g, 19.8 mmol) in 80 ml of 4M hydrochloricacid was refluxed on an oil bath for 1 h. The cooled mixture wasfiltered, and the precipitate was washed with water and ethanol.Recrystallization from ethanol with decolourising charcoal afforded 1.0g (30%) of the title compound; m.p.>300° C.; IR (KBr): 3500-2200, 1690cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 4.48 (s, 3H, CH₃), 7.25 (d, J=9 Hz, 1H, ArH),7.60 (d, J=9 Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.47 (broad s, 1H,OH).

EXAMPLE 117,8-Dihydroxy-2-methyl-4-nitro-2H-1,2,3-triazolo[4,5-f]quinoxaline

Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added to anice-cooled solution of7,8-dihydroxy-2-methyl-2H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6mmol). The mixture was stirred at 0° C. for 11/2 h, then at roomtemperature for 4 h and finally poured into ice/water. The resultingsolution was extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and concentrated to dryness giving 0.27 g (22%)of the nitro compound; m.p.>300° C.; IR (KBr): 1700 cm⁻¹ ; ¹ H-NMR(DMSO-d₆): 4.63 (s, 3H, CH₃), 8.15 (s, 1H, ArH), 12.1 (broad s, 1H, OH),13.0 (broad s, 1H, OH).

EXAMPLE 12 7,8-Dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of 4,5-diamino-1-methylbenzotriazole (1.2 g, 7.4 mmol) andoxalic acid dihydrate (1.2 g, 9.6 mmol) in 40 ml of 4M hydrochloric acidwas refluxed on an oil bath for 2 h and allowed to cool. The resultingprecipitate was collected by filtration and washed with water andethanol to give 1.46 g (91%) of the title compound; m.p.>300° C.; IR(KBr): 1700 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 4.32 (s, ³ H, CH₃), 7.33 (d, J=9Hz), 1H, ArH), 7.55 (d, J=9 Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.67(broad s, 1H, OH).

EXAMPLE 137,8-Dihydroxy-3-methyl-4-nitro-3H-1,2,3-triazolo[4,5-f]quinoxaline

Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was addedportionwise to a stirred solution of7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6mmol) in 20 ml of conc. sulfuric acid at 0° C. After 1 h the ice bathwas removed and the mixture was stirred over night at room temperature.Then an additional amount of potassium nitrate (0.47 g) was added andstirring was continued over night at room temperature. The solution waspoured into ice/water and the precipitated solid was collected, washedwith water, and dried to give 1.0 g (83%) of the pure nitro compound;m.p.>300° C.; IR (KBr): 1710 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 4.50 (s, 3H,CH₃), 8.18 (s, 1H, ArH), 12.13 (broad s, 1H, OH), 13.17 (broad s, 1H,OH).

EXAMPLE 14 4-Amino-7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxaline

A solution of7,8-dihydroxy-3-methyl-4-nitro-3H-1,2,3-triazolo[4,5-f]quinoxaline (0.78g, 3 mmol) in ethanol was hydrogenated at atmospheric pressure and roomtemperature in the presence of 5% palladium-on-charcoal. The catalystand solid was removed by filtration and washed with ethanol andN,N-dimethylformamide. The combined filtrate was concentrated to drynessgiving 30 mg (4%) of the pure amino compound; m.p.>360° C.; IR (KBr):1680, 1620 cm⁻¹. The solid residue containing the catalyst was nowtreated with hot 2N sodium hydroxide, filtered while hot, andreprecipitated with 4M acetic acid to give the amino compound as agelatinous product, which was used in the subsequent Sandmeyer reactionwithout further purification.

EXAMPLE 154-Cyano-7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo-4,5-f]quinoxaline

The 4-amino-7,8-dihydroxy-3-methyl-3H-1,2,3-triazolo[4,5-f]quinoxalineisolated above was dissolved in 3 ml of conc. sulfuric acid and cooledon an ice bath. Water (10 ml) was carefully added and the resultingsuspension was diazotised with sodium nitrite (0.24 g, 3.4 mmol) in 5 mlof water. After stirring at 0° C. for 30 min, the diazo-suspension wasadjusted to pH 7 with saturated aqueous sodium hydrogen carbonate, and asolution of potassium tetracyanonickelate (1.7 g) in 20 ml of water wasadded in one portion. Stirring was continued for 1 h at 0° C., then themixture was heated on a steam-bath for 30 min, and cooled. The resultingprecipitate was collected by filtration and washed with water.Extraction of the solid with methanol on a Soxhlet apparatus afforded0.16 g of the cyano compound; m.p. 370° C. dec.; IR (KBr): 2210, 1670CM⁻¹ ; ¹ H-NMR (DMSO-D₆) 4.33 (s, ³ H, CH₃), 7.57 (s, 1H, ArH), noexchangeable protons could be seen, due to low solubility of thecompound; MS (m/z): M⁺ =242.

EXAMPLE 16 7,8-Dihydroxythiazolo[5,4-f]quinoxaline

A solution of 6,7-diaminobenzothiazole (1.3 g, 7.9 mmol) and oxalic aciddihydrate (1.3 g, 10.3 mmol) in 40 ml of 4M hydrochloric acid wasrefluxed on an oil bath for 11/2 h, and cooled. The resultingprecipitate was collected by filtration and washed successively withwater and ethanol to give 1.52 g (88%) of the title compound; m.p.>360°C.; IR (KBr): 1700 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): ca. 6.3 (very broad s, 1H,OH), 7.40 (d, J=9 Hz, 1H, ArH), 7.87 (d, J=9 Hz, 1H, ArH), 9.33 (s, 1H,H-2), 12.07 (broad s, 1H, OH).

EXAMPLE 17 7,8-Dihydroxy-4-nitrothiazolo[5,4-f]quinoxaline

Finely powdered potassium nitrate (92 mg, 0.9 mmol) was added to astirred and ice-cooled solution of7,8-dihydroxythiazolo[5,4-f]quinoxaline (0.20 g, 0.9 mmol) in 5 ml ofconc. sulfuric acid. The mixture was stirred at 0° C. for 30 min, thenat room temperature for 4 h, and finally poured into ice/water. Theresulting precipitate was isolated by filtration, washed with water, anddried giving 0.15 g (62%) of the nitro compound; m.p.>360° C., IR (KBr):1680 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 8.06 (s, 1H, ArH), 9.53 (s, 1H, ArH),12.23 (broad s, 1H, OH), 12.76 (broad s, 1H, OH).

EXAMPLE 18 a. 5-Amino-2-ethoxycarbonylbenzo[b]thiophene

A suspension of 2-ethoxycarbonyl-5-nitrobenzo[b]thiophene (5.0 g, 20mmol) in 500 ml of ethanol was hydrogenated in the presence of 1.8 g of5% palladium-on-charcoal at room temperature and atmospheric pressureuntil the required volume of hydrogen (ca. 1.4 l) had been taken up. Thecatalyst was removed by filtration and washed with ethanol. The filtratewas concentrated to dryness to give 4.2 g (95%) of the amino compound,m.p. 75°-78° C.; ¹ H-NMR (DMSO-d₆): 1.32 (t, J=7 Hz, ³ H, CH₃), 4.30 (q,J=7 Hz, 2H, CH₂), 5.22 (broad s, 2H, NH₂), 6.87 (dd, J=9, 2 Hz, 1H,H-6), 7.05 (d, J=2 Hz, 1H, H-4), 7.62 (d, J=9 Hz, 1H, H-7), 7.87 (s, 1H,H- 3).

b. 5-Ethoxalylamino-2-ethoxycarbonyl-4-nitrobenzo[b]thiophene

To a stirred solution of 5-amino-2-ethoxycarbonylbenzo[b]thiophene (1.0g, 4.5 mmol) and dry triethylamine (0.63 ml, 4.5 mmol) in 7 ml of drytetrahydrofuran was added dropwise a solution of ethyl oxalylchloride(0.50 ml, 4.5 mmol) in 5 ml of dry tetrahydrofuran under ice-cooling.The reaction mixture was stirred for 1 h at 0° C., and filtered. Thefiltrate was concentrated to dryness giving 1.46 g (quantitative) of theethoxalylamino compound. The crude product was nitrated without furtherpurification by adding 0.96 g (3 mmol) portionwise to 10 ml ofice-cooled 80% nitric acid and stirring the mixture at 0° C. for 30 min.Then the mixture was poured into ice-water and the resulting yellowprecipitate was isolated by filtration and washed with water to give0.94 g (86%) of the title compound, m.p. 140°-145° C.; ¹ H-NMR(DMSO-d₆): 1.35 (t, J=7 Hz, 6H, 2CH₃), 4.35 (q, J=7 Hz, 2H, CH₂), 4.37(q, J=7 Hz, 2H, CH₂), 7.92 (d, J=9 Hz, 1H, ArH), 8.17 (s, 1H, H-3), 8.43(d, J=9 Hz, 1H, ArH), 11.42 (broad s, 1H, NH).

c. 8-Ethoxycarbonyl-2,3-dihydroxythieno[3,2-f]quinoxaline

A solution of 5-ethoxalylamino-2-ethoxycarbonyl-4-nitrobenzo[b]thiophene(0.84 g, 2.3 mmol) in ethanol was hydrogenated at atmospheric pressureand room temperature in the presence of 0.55 g of 5%palladium-on-charcoal. The catalyst was removed by filtration and washedwith ethanol. The filtrate was heated to reflux for 11/2 h, and cooled.The resulting precipitate was collected by filtration and washed withethanol to give 0.42 g (63%) of the title compound, m.p. 357°-361° C.;IR (KBr): 1680 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 1.36 (t, J=7 Hz, ³ H, CH₃),4.37 (q, J=7 Hz, 2H, CH₂), 7.33 (d, J=9 Hz, 1H, ArH), 7.73 (d, J=9 Hz,1H, ArH), 8.83 (s, 1H, H-9), 12.06 and 12.30 (2 broad s, 2H, 2 OH).

EXAMPLE 19 8-Carboxy-2,3-dihydroxythieno[3,2-f]quinoxaline

8-Ethoxycarbonyl-2,3-dihydroxythieno[3,2-f]quinoxaline (2.0 g, 6.9 mmol)was stirred in 30 ml of 2N sodium hydroxide at room temperature for 2 h.The solution was filtered, and after acidification of the filtrate with4M hydrochloric acid, the resulting precipitate was collected byfiltration and washed with water. The crude product was dissolved in 2Nsodium hydroxide and reprecipitated with 4M hydrochloric acid to give0.94 g (52%) of the carboxylic acid, m.p.>350° C. dec.; IR (KBr):3300-2200, 1690 cm⁻¹.

EXAMPLE 20 4-Chloro-7,8-dihydroxy-1,2,5-selenodiazolo[3,4-f]quinoxaline

A solution of selenium dioxide (0.22 g, 2 mmol) in 20 ml of water wasadded to a suspension of 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline(0.45 g, 2 mmol) in 20 ml of ethanol and the mixture was refluxed on anoil bath for 11/2 h. After cooling, the deposited solid was collected byfiltration and washed with water and ethanol. The crude product wasboiled in 200 ml of 2N sodium hydroxide, filtered while hot, andreprecipitated with 4M hydrochloric acid to give 0.46 g (76%) of theyellow title compound, m.p.>300° C., ¹ H-NMR (DMSO-d₆) 7.90 (s, 1H,H-5), 11.93 and 12.10 (2 broad s, 2H, 2 OH).

EXAMPLE 21 7,8-Dihydroxy-4-sulfamoylthiazolo[5,4-f]quinoxaline

7,8-Dihydroxythiazolo[5,4-f]quinoxaline (0.44 g, 2 mmol) was addedportionwise to 2 ml of chlorosulfonic acid with stirring at roomtemperature. Then the mixture was stirred at 150° C. for 5 h, and leftover night at room temperature. The solution was added dropwise to 50 gof crushed ice with stirring. The resulting solid was collected byfiltration after 1 h and washed with ice-water and a small amount ofethanol and ether, affording 0.30 g (47%) of crude4-chlorosulfonyl-7,8-dihydroxythiazolo[5,4-f]quinoxaline. The crudeproduct was stirred with 25 ml of aqueous ammonium hydroxide (25%) for20 min at room temperature and at 100° C. for 10 min. Nitrogen wasbubbled through the hot solution for 5-10 min and after cooling to 0° C.the solution was acidified to pH 1 with 4M hydrochloric acid. Theresulting prcipitate was isolated by filtration and dissolved in 150 mlof hot N,N-dimethylformamide. A solid impurity was removed from the hotsolution by filtration, and after treatment with charcoal the solutionwas cooled and evaporated to dryness. The residue was taken up with 15ml of hot 2N sodium hydroxide, the resulting solution was treated withcharcoal, cooled to 0° C. and acidified with 4M hydrochloric acid. Theprecipitated solid was isolated by centrifugation and washed with waterand ethanol to give 60 mg (21%) of the title compound, m.p.>400° C.; IR(KBr): 1710, 1690 cm⁻¹ ; ¹ H-NMR (DMSO-d₆): 7.28 (broad s, 2H, NH₂),7.90 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.17 (broad s, 1H, OH), 12.60(broad s, 1H, OH).

EXAMPLE 22 a. 6-Chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline

A solution of 10 g (47,3 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxalinein 200 ml 0,5N sodium hydroxide was ice-cooled, and then 30 ml (0,36mmol) ethyl chloroformate was added. Stirring was continued at 0° C. for1 h and at 25° C. for 1 h. To the reaction mixture was added 1Nhydrochloric acid to pH 2-3, and the precipitated product was filteredoff and washed with water to give 12 g of a crude product.Recrystallization (dimethylsulfoxide-0,5N hydrochloric acid) gave 10 g(75%) 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline, m.p.>300°C. NMR (DMSO-d₆) 11.9 (2H, broad s), 8.9 (1H, broad s), 7.37 (1H,s),7.17 (1H,s), 4.1 (2H,q), 1.28 (3H,t).

b. 7-Chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline

To an ice-cooled mixture of 50 ml 100% nitric acid and 100 ml glacialacetic acid was added gradually 10 g6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline. Stirring wascontinued at 0° C. for 90 min. The reaction mixture was poured into 500ml ice-water to give 10 g (86%)7-chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline asyellow crystals, m.p.>300° C. NMR (DMSO-d₆): 12.2 (1H, broad s), 11.7(1H, broad m), 9.3 (1H, broad s), 7.33 (1H,S), 4.0 (2H,q), 1.2 (3H,t).

c. 6-Amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline

A mixture of 5 g (15,4 mmol)7-chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline and 10 gpotassium hydroxide in 60 ml 2-methoxyethanol was refluxed for 15 min.After cooling to 25° C., the reaction mixture was added 20 ml2-methoxyethanol and 40 ml ether. The precipitated black product wasfiltered off and washed with ether. The crude product was dissolved in100 ml water. Addition of 4N hydrochloric acid to pH 5-6 gave 3,4 g(87%) 6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline as red crystals,m.p.>300° C. NMR (DMSO-d₆) 12.3 (2H, broad m), 7.40 (1H,s), 6.8 (2H,broad s).

d. 5,6-Diamino-7-chloro-2,3-dihydroxyquinoxaline

A solution of 3 g (11,9 mmol)6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline in a mixture of 80 mldimethylformamide and 7,5 ml triethylamine was hydrogenated at atm.pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture wasfiltered and evaporated in vacuo. The residue was stirred with 100 mlwater, added 4N hydrochloric acid to pH 5-6, and the precipitate wasfiltered off to give 2,1 g of a crude product. Recrystallization(dimethylformamide-methanol) gave 1,95 g (74%)5,6-diamino-7-chloro-2,3-dihydroxy-quinoxaline, m.p.>300° C. NMR(DMSO-d₆): 11.6 (1H, broad s), 11.0 (1H, broad m), 6.47 (1H,s), 5.1 (2H,broad s), 4.6 (2H, broad s).

e. 4-Chloro-7,8-dihydroxy-1H-imidazo(4,5-f)quinoxaline

A mixture of 0,3 g (1,35 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml formic acid wasrefluxed for 2 h. After cooling to 25° C., the reaction mixture waspoured into 30 ml water to give 0,21 g (67%)4-chloro-7,8-dihydroxy-1H-imidazo(4,5-f)quinoxaline, m.p.>300° C. NMR(DMSO-d₆): 7.37 (1H,s), 6.70 (1H,s).

EXAMPLE 23 a. 4,5-Diethoxalylaminobenzofurazan

To a solution of 3,6 g (24,0 mmol) 4,5-diaminobenzofurazan in 200 ml drytetrahydrofuran was added 6,8 ml (48,8 mmol) dry triethylamine. Asolution of 5,4 ml (48,0 mmol) ethoxalylchloride in 50 ml drytetrahydrofuran was added dropwise, and the reaction mixture was leftwith stirring at 20° C. for 3h. The mixture was filtered and evaporatedto give an oil. The crude product was stirred with methanol to give 3,4g (81%) 4,5-diethoxalylaminobenzofurazan, m.p. 175,0° C.

b. 7,8-Dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline

A mixture of 2,5 g (7,1 mmol) 4,5-diethoxalylaminobenzofurazan and 20 ml1N hydrochloric acid was refluxed for 3 h. After cooling to 0° C., theprecipitate was filtered off and washed with water to give 1,4 g (97%)7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C. NMR(DMSO-d₆) 12,8 (1H broad s). 12.3 (1H, broad s), 7.70 (1H,d). 7.37(1H,d).

EXAMPLE 24 7,8-Dihydroxy-4-nitro-1,2,5-oxadiazolo(3,4-f)quinoxaline

A solution of 0,4 g (2 mmol)7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline in 20 ml concentratedsulfuric acid (95-97%) was ice-cooled and then added 0,2 g (2 mmol)potassium nitrate. Stirring was continued at 0° C. for 30 min. and thenat 25° C. for 3 h. The reaction mixture was poured into 100 mlice-water. Addition of 10N sodium hydroxide to pH 2-3 gave a precipitate(0,44 g). The crude product was recrystallized (methanol-acetone-water)to give 0,38 g (78%) of7,8-dihydroxy-4-nitro-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C.NMR (DMSO-d₆) 12.4 (2H, broad s), 8.47 (1H,s).

EXAMPLE 25 a. 6-Azido-7-chloro-2,3-dihydroxyquinoxaline

A solution of 2 g (9,6 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxalinein 40 ml 50% fluoroboric acid was added 100 ml water, filtered and thenice-cooled. A solution of 0,68 g (9,9 mmol) sodium nitrite in 20 mlwater was added, and after stirring at 0° C. for 15 min. 0,68 g (1,0mmol) sodium azide dissolved in 20 ml water was added. Stirring wascontinued at 25° C. for 2 h. The precipitate was filtered off and washedwith water to give 1,8 g (80%)6-azido-7-chloro-2,3-dihydroxyquinoxaline. IR (KBr): 2100 cm⁻¹ (N₃). NMR(DMSO-d₆): 11.7 (2H, broad s), 7.03 (1H,s), 6.93 (1H,s).

b. 6-Azido-7-chloro-2,3-dihydroxy-5-nitroquinoxaline

15 ml 89% nitric acid was ice-cooled and then gradually added 1 g (4,2mmol) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. After stirring at 0° C.for 15 min, the reaction mixture was poured into 100 ml ice-water. Thecrude product was recrystallized (acetone-methanol-water) to give 0,95 g(80%) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinooxaline. IR (KBr): 2450cm⁻¹ (N₃). NMR (DMSO-d₆) 12.3 (2H, broad s), 7.07 (1H,s).

c. 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide

A mixture of 1 g (3,5 mmol)6-azido-7-chloro-2,3-dihydroxy-5-nitroquinoxaline and 15 ml xylene wasrefluxed for 3 h. After cooling to 25° C. the precipitate was filteredoff and washed with toluene and ether to give 0,86 g (96%)4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide,m.p.>300° C. NMR (DMSO-d₆): 12.6 (1H, broad s), 12.0 (1H, broad s), 7.10(1H,s).

EXAMPLE 264-Chloro-7,8-dihydroxy-2-trifluoromethyl-1H-imidazo(4,5-f)quinoxaline

A mixture of 0,3 g (1,35 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml trifluoroaceticacid was refluxed for 3 h. After cooling to 0° C., the precipitatedproduct was filtered off and washed with ice-cooled trifluoroacetic acidand ether to give 0,28 g (68%)4-chloro-7,8-dihydroxy-2-trifluoromethyl-1H-imidazo(4,5-f)quinoxaline,m.p.>300° C. NMR (DMSO-d₆) 7.10 (1H,s).

EXAMPLE 27 a. 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline

To a solution of 0,6 g (2,4 mmol)4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide in amixture of 14 ml ethanol and 3 ml dimethylformamide was added 0,9 ml(5,3 mmol) triethyl phosphite. The mixture was refluxed for 4 h, andthen evaporated in vacuo. The residue was stirred with water and thenwith ether-ethyl acetate (5:1) to give 0,4 g (71%)4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C.NMR (DMSO-d₆ +D₂ O): 7.40 (1H,s).

EXAMPLE 28 6-Chloro-2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline

A mixture of 0,5 g (2,24 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 10 ml water was at 50°C. added a solution of 0,4 g (4,6 mmol) 2,3-butanedione in 5 ml water.The reaction mixture was stirred at 50° C. for 24 h. After cooling to25° C., the precipitate was filtered off and washed with water andethanol to give 0,3 g (50%)6-chloro-2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300°C. NMR (DMSO-d₆) 8.47 (1H,s), 2.60 (3H,s), 2.53 (3H,s).

EXAMPLE 29 6-Chloro-2,3-dihydroxypyrazino(2,3-f)quinoxaline

A mixture of 0,5 g (2,24 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 20 ml water was added0,5 ml (3,36 mmol) 40% aqueous glyoxal and 0,35 g (3,36 mmol) sodiumcarbonate. The reaction mixture was stirred at 50° C. for 3 h. Aftercooling to 25° C., the precipitate was filtered off. The crude productwas stirred with water and added 1N hydrochloric acid to pH 2-3 to give0,56 g (100%) 6-chloro-2,3-dihydroxypyrazino(2,3-f)quinoxaline,m.p.>300° C. NMR (DMSO-d₆) 9.0 (2H,s), 7.73 (1H,s).

EXAMPLE 30 4-Chloro-7,8-dihydroxy-2-methyl-1H-imidazo(2,3-f)quinoxaline

A mixture of 0,5 g (2,24 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 0,33 g (3,3 mmol)2,4-pentanedione in 20 ml glacial acetic acid was stirred at 100° C. for30 min. After cooling to 25° C., the precipitate was filtered off andwashed with glacial acetic acid and ether to give 0,53 g (100%)4-chloro-7,8-dihydroxy-2-methyl-1H-imidazo(2,3-f)quinoxaline m.p.>300°C. NMR (DMSO-d₆): 7.0 (1H,s), 2.53 (3H,s).

EXAMPLE 312,3-Dihydroxy-8,10-dimethyl-7H-pyrazino(2,3-g)(1,5)benzodiazepine

A mixture of 0,5 g (2,24 mmol)5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 1,0 g (10 mmol)2,4-pentanedione in 15 ml glacial acetic acid was stirred at 25° C. for20 h. The precipitate was filtered off and washed with ethanol and etherto give 0,43 g (67%)2,3-dihydroxy-8,10-dimethyl-7H-pyrazino(2,3-g)(1,5)benzodiazepine,m.p.>300° C. NMR (DMSO-D₆): 7.07 (2H,s), 2.33 (3H,s), 2.27(3H,s).

EXAMPLE 32 a. 5,6-Diamino-2,3-dihydroxyquinoxaline

A solution of 5,0 g (24,5 mmol)7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline and 6,8 ml (49 mmol)triethylamine in 500 ml dimethylformamide was hydrogenated at atm.pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture wasfiltered and evaporated in vacuo. The residue was stirred with water,and the precipitate was filtered off to give 4,5 g (96%)5,6-diamino-2,3-dihydroxyquinoxaline, m.p.>300° C. NMR (DMSO-d₆) 11.0(2H, broad m), 6.43 (1H,d), 6.23 (1H,d), 4.5 (4H, broad m).

b. 2,3-Dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline

A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and10 ml water was at 50° C. added a solution of 0,45 g (5,2 mmol)2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50°for 4 h. After cooling to 25° C., the precipitate was filtered off andwashed with water. The crude product was dissolved in 2N sodiumhydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give0,4 g (64%) 2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline,m.p.>300° C. NMR (DMSO-d₆): 7.27 (1H,d), 6.93 (1H,d), 2.07 (6H,s).

EXAMPLE 33 7,8-Dihydroxy-2-methyl-1H-imidazo(2,3-f)quinoxaline

A mixture of 0,5 g (2,56 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and0,52 g (5,2 mmol) 2,4-pentanedione in 20 ml glacial acetic acid wasstirred at 100° C. for 1,5 h. After cooling to 25° C., the precipitatewas filtered off and washed with water and ethanol to give 0,56 g (100%)7,8-dihydroxy-2-methyl-1H-imidazo(2,3-f)quinoxaline, m.p.>300° C. NMR(DMSO-d₆): 7,17 (1H,d), 6.93 (1H,d), 2.53 (3H,s).

EXAMPLE 34 2,3-Dihydroxypyrazino(2,3-f)quinoxaline

A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and20 ml water was added 0,6 ml (3,9 mmol) 40% aqueous glyoxal and 0,41 g(3,9 mmol) sodium carbonate. The reaction mixture was stirred at 50° C.for 1,5 h. After cooling to 25° C., the precipitate was filtered off andwashed with water to give 0,49 g. The crude product was dissolved in 2Nsodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7to give 0,2 g (36%) 2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p.>300°C. NMR (DMSO-d₆): 8.30 (1H,d), 8.20 (1H,d), 7.27 (1H,d), 7.0 (1H,d).

EXAMPLE 35 2,3-Dihydroxy-6-nitropyrazino(2,3-f)quinoxaline

To a solution of 0,38 g (1,4 mmol)2,3-dihydroxy-pyrazino(2,3-f)quinoxaline in 25 ml concentrated sulfuricacid was added at 0° C. 0,28 g (2,8 mmol) potassium nitrate. Stirringwas continued at 0° C. for 30 min. and at 25° C. for 24 h. The reactionmixture was poured into 100 ml ice-water. The solution was added 10Nsodium hydroxide to pH 7, and then extracted with ethyl acetate (5×100ml). The combined and dried ethyl acetate phases were evaporated to give0,17 g (47%) 2,3-dihydroxy-6-nitropyrazino(2,3-f)quinoxaline, m.p.>300°C. NMR (DMSO-d₆): 9.10 (2H,s), 8.23 (1H,s).

EXAMPLE 36 2,3-Dihydroxy-8,9-dimethyl-6-nitropyrazino(2,3-f)quinoxaline

To a solution of 0,45 g (1,9 mmol)2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline in 30 mlconcentrated sulfuric acid was added at 0° C. 384 mg (3,8 mmol)potassium nitrate. Stirring was continued at 0° C. for 30 min. and at25° C. for 24 h. The reaction mixture was poured into 150 ml ice-water.The solution was added 10N sodium hydroxide to pH 7, and then extractedwith ethyl acetate (5×100 ml). The combined and dried ethyl acetatephases were evaporated to give 0,18 g (33%)2,3-dihydroxy-8,9-dimethyl-6-nitropyrazino(2,3-f)quinoxaline, m.p.>300°C. NMR (DMSO-d₆) 8.07 (1H,s), 2.77 (3H,s), 2.73 (3H,s).

EXAMPLE 37 a. 4,5-Diethoxalylamino-1,2,5-benzothiadiazole

To a mixture of 2,0 g (12,0 mmol) 4,5-diamino-1,2,5-benzothiadiazole and5,0 ml (32 mmol) dry triethylamine in 100 ml dry tetrahydrofuran wasadded dropwise a solution of 3,0 ml (27 mmol) ethoxalylchloride in 35 mldry tetrahydrofuran. Stirring was continued at 25° C. for 2 h. Thereaction mixture was filtered and evaporated in vacuo. The residue wasstirred with water, and the mixture was extracted with ethyl acetate(2×50 ml). The combined and dried ethyl acetate phases were evaporatedto give 3,0 g (68%) 4,5-diethoxalylamino-1,2,5-benzothiadiazole, m.p.168,5° C. NMR (DMSO-d₆): 10.8 (1H, broad s), 10.6 (1H, broad s), 8.03(2H,s), 4.3 (4H,q), 1.33 (6H,t).

b. 7,8-Dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline

A mixture of 1,0 g (2,73 mmol)4,5-diethoxalylamino-1,2,5-benzothiadiazole and 5 ml ethanol and 10 ml1N hydrochloric acid was refluxed for 2 h. The reaction mixture wasadded 10 ml water, cooled to 25° C., and filtered to give 0,57 g (95%)7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline, m.p.>300° C. NMR(DMSO-d₆) 12.5 (1H, broad s), 12.2 (1H, broad s), 7.73 (1H,d), 7.47(1H,d).

EXAMPLE 38 7,8-Dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline

To a solution of 0,4 g (1,8 mmol)7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline in 20 ml concentratedsulfuric acid was added at 0° C. 0,19 g (1,9 mmol) potassium nitrate.Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. Thereaction mixture was poured into 100 ml ice-water to give 0,34 g (71%)7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline as aprecipitate, m.p.>300° C. NMR (DMSO-d₆) 12,3 (1H, broad s), 11.6 (1H,broad s), 8.43 (1H,s).

EXAMPLE 39 2.3-Dihydroxythieno[3,2-f]quinoxaline

A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50ml of 96% ethanol was hydrogenated at room temperature and atm. pressurein the presence of 5% palladium-on-carbon until the theoretical amountof hydrogen was absorbed. The catalyst was filtered off, and thefiltrate was acidified with 1N hydrochloric acid and evaporated todryness. The residue was refluxed with oxalic acid dihydrate (0.40 g,3.1 mmol) in 25 ml of 4M hydrochloric acid for 2 h. The mixture wascooled, and the precipitated solid was isolated by filtration, washedwith water, ethanol and ether, and dried. The crude product wasdissolved in a minimum amount of 2N sodium hydroxide, treated withdecolourising charcoal, and filtered. The filtrate was acidified with 4Mhydrochloric acid and the resulting precipitate was collected byfiltration, washed with water, ethanol and ether to give 0.22 g (39%) ofthe thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm⁻¹ ; H-NMR(DMSO-d₆ ) 7.13 (d,J=9 Hz, 1H, ArH), 7.62 (D,J=9 Hz, 1H, ArH), 7.72(d,J=5 Hz, 1H, ArH), 7.95 (d,J=5 Hz, 1H, ArH); MS m/z: 218 (M⁺, 100%).

The pharmaceutical preparations or compositions comprising the compoundsof the invention may be administered to humans or animals by oral orparenteral route.

An effective amount of the active compound or apharmaceutically-acceptable salt thereof may be determined in accordancewith the usual factors, such as the nature and severity of the conditionand the weight of the mammal requiring treatment.

Conventional excipients are such pharmaceutically-acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose, and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salt for influencing osmotic pressure,buffers and/or coloring substances and the like which do notdeleteriously react with the active compounds.

Injectable solutions or suspensions, preferably aqueous solutions withthe active compound dissolved in polyhydroxylated castor oil, areparticularly suitable for parenteral administration.

Ampoules are conveniently unit dosages.

Tablets, dragees, or capsules containing talc and/or a carrier or binderor the like are particularly suitable for oral administration. Thecarrier preferably is lactose and/or corn starch and/or potato starch.

A syrup, elixir, or the like can be used in the cases where a sweetenedvehicle can be employed or is desired.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 10-200 mg of active ingredient in or together with apharmaceutically-acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,when administered to patients, e.g., humans, as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Core:                                                                         Active compound (as free compound                                                                       100    mg                                           or salt thereof)                                                              Colloidal silicon dioxide (Aerosil ®)                                                               1.5    mg                                           Cellulose, microcryst. (Avicel ®)                                                                   70     mg                                           Modified cellulose gum (Ac-Di-Sol ®)                                                                7.5    mg                                           Magnesium stearate        1      mg                                           Coating:                                                                      HPMC approx.              9      mg                                           *Mywacett 9-40 T ® approx.                                                                          0.9    mg                                           ______________________________________                                         *Acylated monoglyceride used as plasticizer for filmcoating              

The free compounds of the present invention which form alkali metal oralkaline earth metal salts may be employed in such salt form. Suchalkali metal or earth alkali metal salts are ordinarily formed byreacting the dihydroxyquinoxaline compound with an equivalent amount orexcess of the selected alkali metal or earth alkali metal as thehydroxide, frequently and suitably by admixture in the presence of aneutral solvent, from which the salt may be precipitated or recovered inother conventional manner, e.g., by evaporation. Administration of acompound of the invention is often preferably in the form of apharmaceutically-acceptable water-soluble alkali metal or earth alkalimetal salt thereof, and orally, rectally, or parenterally in the form ofa pharmaceutical composition wherein it is present together with apharmaceutically-acceptable liquid or solid carrier or diluent.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids, such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceutical compositionand unit dosage forms thereof may comprise conventional ingredients inconventional proportions, with or without additional active compounds orprinciples, and such unit dosage forms may contain any suitableeffective glutamate antagonistic, amount of the active ingredientcommensurate with the intended daily dosage range to be employed.Tablets containing fifty (50) milligrams of active ingredient or, morebroadly, ten (10) to two hundred (200) milligrams, per tablet, areaccordingly suitable representative unit dosage forms.

Due to their high degree of glutamate antagonistic activity and theirlow toxicity, together presenting a most favorable therapeutic index,the compounds of the invention may be administered to a subject, e.g., aliving animal body, in need of such glutamate antagonist treatment,elimination, alleviation, or amelioration of an indication which issensitive to a change in the glutamate receptor condition, e.g.,epilepsy, psychosis, dementia, convulsion, or muscle rigidity, oftenpreferably in the form of an alkali metal or earth alkali metal saltthereof, concurrently, simultaneously, or together with apharmaceutically-acceptable carrier or diluent, especially andpreferably in the form of a pharmaceutical composition thereof, whetherby oral, rectal, or parenteral (including subcutaneous) route, in aneffective amount. Suitable dosage ranges are 1-500 milligrams daily,preferably 10-200 milligrams daily, and especially 50-100 milligramsdaily, depending as usual upon the exact mode of administration, form inwhich administered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and the preference and experience of the physician orveterinarian in charge. Such method of treating may be described as thetreatment of an indication caused by or related to hyperactivity of theexcitatory neurotransmitters, in a subject in need thereof, whichcomprises the step of administering to the said subject aneurologically-effective amount of a glutamate antagonistic heterocycliccompound of the invention.

In conclusion, from the foregoing, it is apparent that the presentinvention provides novel neurologically-effective glutamate antagonisticheterocyclic compounds and salts thereof, having advantageous andunpredictable properties, as well as novel pharmaceutical compositionsthereof and method of treating therewith, all possessed of the foregoingmore specifically-enumerated characteristics and advantages.

It is to be understood that the invention is not to be limited to theexact details of operation, or to the exact compositions, methods,procedures, or embodiments shown and described, as obvious modificationsand equivalents will be apparent to one skilled in the art, and theinvention is therefore to be limited only by the full scope of theappended claims.

We claim:
 1. A heterocyclic compound selected from those having the formula I ##STR5## wherein R² is hydrogen, NO₂, NH₂, CN, halogen, or SO₂ NH₂ ;--X--Y--Z-- is selected from --S--CH═N--,--N═CH--S-- and a pharmaceutically-acceptable salt thereof.
 2. A pharmaceutical composition comprising as active glutamate antagonistic component a heterocyclic compound according to claim 1 and a pharmaceutically-acceptable carrier.
 3. A pharmaceutical composition according to claim 2 in the form of an oral dosage unit containing about 10-200 mg of the active compound.
 4. A method of treating hyperactivity of the excitatory neurotransmitters, in a subject in need thereof, which comprises the step of administering to the said subject a neurologically-effective, glutamate antagonistic, amount of a heterocyclic compound of claim
 1. 5. A compound according to claim 1 which is 7,8-dihydroxythiazolo[5,4-f]quinoxaline.
 6. A compound according to claim 1 which is 7,8-dihydroxy-4-nitrothiazolo[5,4-f]quinoxaline.
 7. A compound according to claim 1 which is 7,8-dihydroxy-4-sulfamoylthiazolo[5,4-f]quinoxaline. 